Safety and Immunogenicity of SARS-CoV-2 Vaccination in Children with a History of MIS-C

Background. Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare sequela that typically develops 2-6 weeks after SARS-CoV-2 infection. According to CDC recommendations, children who recover from MIS-C should be vaccinated 90 days after diagnosis, but safety and immunogenicity data are lacking. Our aim was to evaluate the safety and immunogenicity of one dose of the BNT162b2 vaccine in children with a history of MIS-C. Methods. We conducted a longitudinal study of children with MIS-C admitted to Monroe Carell Jr. Children's Hospital at Vanderbilt from 7/11/2020 to 3/23/2022. Children were eligible if they met CDC's MIS-C criteria and had blood collected before and after SARS-CoV-2 vaccination. Clinical data were obtained from medical records and injection site and systemic reactions were recorded for a week following SARS-CoV-2 vaccination via memory aids. IgG against SARS-CoV-2 nucleocapsid (N), spike receptor-binding domain (RBD), and spike extracellular domain (ECD)was detected using an enzyme-linked immunosorbent assay. The first anti-RBD and anti-ECD levels prevaccination and post vaccination were compared using the paired-samples t-test. Results. Seven children were included, of whom five were male and five were non-Hispanic White. The first blood sample was collected 3-44 days following admission. The median age at admission was 15.8 years (IQR, 10.5-14.7 years), and the median time from admission to vaccination was 7 months (IQR, 6-8 months). Five children each had injection site or systemic reactions (Figure 1);the majority were mild or moderate and occurred within 2 days of vaccination. Children were followed for a median of 5.6 months (4.3-6.2 months) postvaccination;none developed MIS-C recurrence. Following vaccination, mean anti-RBD and anti-ECD levels increased by 2.0 (1.2-2.9;p < 0.001) and 1.9 (1.2-2.6;p < 0.001) absorbance units, respectively (Figure 2). A sensitivity analysis excluding children with antibody evidence of reinfection (increase in anti-N level >= 0.5) showed similar results. Conclusion. SARS-CoV-2 vaccination is safe and immunogenic in children with a history of MIS-C, with no documented recurrence of MIS-C-like illness. Further studies are needed to determine the optimal timing, safety, and immunogenicity of vaccination following MIS-C.

Circulation of Rhinovirus/Enterovirus Respiratory Infections in Children during 2020-21 in the United States

Background. Sharp declines in influenza and respiratory syncytial virus (RSV) circulation across the U.S. have been described during the pandemic in temporal association with community mitigation for control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to determine relative frequencies of rhinovirus/ enterovirus (RV/EV) and other respiratory viruses in children presenting to emergency departments or hospitalized with acute respiratory illness (ARI) prior to and during the COVID-19 pandemic. Methods. We conducted a multi-center active prospective ARI surveillance study in children as part of the New Vaccine Surveillance Network (NVSN) from December 2016 through January 2021. Molecular testing for RV/EV, RSV, influenza, and other respiratory viruses [i.e., human metapneumovirus, parainfluenza virus (Types 1-4), and adenovirus] were performed on specimens collected from children enrolled children. Cumulative percent positivity of each virus type during March 2020-January 2021 was compared from March-January in the prior seasons (2017-2018, 2018-2019, 2019-2020) using Pearson's chi-squared. Data are provisional. Results. Among 69,403 eligible children, 37,676 (54%) were enrolled and tested for respiratory viruses. The number of both eligible and enrolled children declined in early 2020 (Figure 1), but 4,691 children (52% of eligible) were enrolled and tested during March 2020-January 2021. From March 2020-January 2021, the overall percentage of enrolled children with respiratory testing who had detectable RV/EV was similar compared to the same time period in 2017-2018 and 2019-2020 (Figure 1, Table 1). In contrast, the percent positivity of RSV, influenza, and other respiratory viruses combined declined compared to prior years, (p< 0.001, Figure 1, Table 1). Figure 1. Percentage of Viral Detection Among Enrolled Children Who Received Respiratory Testing, New Vaccine Surveillance Network (NVSN), United States, December 2016 - January 2021 Table 1. Percent of Respiratory Viruses Circulating in March 2020- January 2021, compared to March-January in Prior Years, New Vaccine Surveillance Network (NVSN), United States, March 2017 - January 2021 Conclusion. During 2020, RV/EV continued to circulate among children receiving care for ARI despite abrupt declines in other respiratory viruses within this population. These findings warrant further studies to understand virologic, behavioral, biological, and/or environmental factors associated with this continued RV/EV circulation.

Persistence of Long COVID in SARS-CoV-2 Confirmed Cases One-Year Post Infection

Background. Regardless of severity of acute SARS-CoV-2 illness, adults infected with SARS-CoV-2 are at risk for post-acute sequelae of COVID-19. Long COVID is typically classified as symptoms lasting greater than four weeks post-infection. We aimed to evaluate the frequency of resolved and unresolved long COVID symptoms in adults residing in greater Nashville, TN. Methods. We conducted a longitudinal cohort study of SARS-CoV-2-positive and exposed individuals from March 20 to May 15, 2020. Participants for this analysis were included if: 1) ≥18 years;2) SARS-CoV-2 positive by molecular or antibody testing;and 3) completed a one-year visit. Demographic and illness information were collected at enrollment, and long COVID symptoms were systematically collected at the one-year survey. Long COVID symptoms are defined as an adult experiencing at least one of the following symptoms four weeks post-infection: fatigue, confusion, loss of smell or taste, shortness of breath, chest pain, cough, muscle aches, inability to exercise, or heart palpitations. Unresolved symptoms are defined as an individual with long COVID still experiencing symptoms at the one-year visit. Results. A total of 115 adults enrolled and completed the one-year survey, of which 63 (54.8%) were SARS-CoV-2-positive, with one asymptomatic individual. Of SARS-CoV-2-positive symptomatic adults, 32 (51%) were female, 5 (88%) were of Hispanic ethnicity, and 58 (92%) were white. At the one-year visit, 33 (52%) reported having long COVID, of which 17 (52%) reported having unresolved symptoms. Fatigue (89%), headache (89%), muscle aches (79%), and cough (77%) were the most common symptoms reported at illness onset (Figure 1). Among 33 adults with long COVID, fatigue (42%), loss of smell (39%), and loss of taste (33%) were most common (Figure 2A). In the 17 individuals with unresolved symptoms, loss of smell (29%) and loss of taste (24%) were commonly reported (Figure 2B). Figure 1. COVID-19 symptoms reported at enrollment (n=62) Figure 2. Long COVID (symptoms lasting ≥ 4 weeks) (n=33) (A) and unresolved long COVID symptoms one-year post-infection (n=17) (B) reported on the one-year survey Conclusion. Half of the adults in our cohort reported long COVID symptoms, with more than quarter of symptoms persisting one-year post-illness. Our findings support that prolonged symptoms up to year after SARS-CoV-2 exposure occur, and future studies should investigate the residual impacts of long COVID symptoms and conditions.

Identification of Early Features to Differentiate Hospitalized Children Admitted for Suspected MIS-C from Alternative Diagnoses

Background. Multi-system inflammatory syndrome in children (MIS-C) is a rare consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MIS-C shares features with common infectious and inflammatory syndromes and differentiation early in the course is difficult. Identification of early features specific to MIS-C may lead to faster diagnosis and treatment. We aimed to determine clinical, laboratory, and cardiac features distinguishing MIS-C patients within the first 24 hours of admission to the hospital from those who present with similar features but ultimately diagnosed with an alternative etiology. Methods. We performed retrospective chart reviews of children (0-20 years) who were admitted to Vanderbilt Children's Hospital and evaluated under our institutional MIS-C algorithm between June 10, 2020-April 8, 2021. Subjects were identified by review of infectious disease (ID) consults during the study period as all children with possible MIS-C require an ID consult per our institutional algorithm. Clinical, lab, and cardiac characteristics were compared between children with and without MIS-C. The diagnosis of MIS-C was determined by the treating team and available consultants. P-values were calculated using two-sample t-tests allowing unequal variances for continuous and Pearson's chi-squared test for categorical variables, alpha set at < 0.05. Results. There were 128 children admitted with concern for MIS-C. Of these, 45 (35.2%) were diagnosed with MIS-C and 83 (64.8%) were not. Patients with MIS-C had significantly higher rates of SARS-CoV-2 exposure, hypotension, conjunctival injection, abdominal pain, and abnormal cardiac exam (Table 1). Laboratory evaluation showed that patients with MIS-C had lower platelet count, lymphocyte count and sodium level, with higher c-reactive protein, fibrinogen, B-type natriuretic peptide, and neutrophil percentage (Table 2). Patients with MIS-C also had lower ejection fraction and were more likely to have abnormal electrocardiogram. Conclusion. We identified early features that differed between patients with MIS-C from those without. Development of a diagnostic prediction model based on these early distinguishing features is currently in progress.

Comparison of Demographics and Clinical Characteristics of Multisystem Inflammatory Syndrome in Children and Kawasaki Disease

Background. Multisystem inflammatory syndrome in children (MIS-C) is an illness associated with recent SARS-CoV-2 infection or exposure. Kawasaki disease (KD), a vasculitis with an unknown etiology, has overlapping clinical presentation with MIS-C, making it difficult to clinicians for distinguish between them. Therefore, we aimed to compare demographic, laboratory, and clinical characteristics between MIS-C and KD in hospitalized children in Nashville, TN. Methods. We conducted a single-center retrospective chart review for hospitalized children under 18 years who met American Heart Association criteria for KD and were treated with intravenous immunoglobulin from May 2000 to December 2019, and children meeting the CDC criteria for MIS-C from July 2020 to May 2021. Data ion for patients' demographics, clinical presentation, laboratory values and imaging results was performed. Pearson's chi-squared test for categorical variables and Wilcoxon rank sum test for continuous variables, with alpha=5%, were used to compare groups. Results. A total of 603 KD and 52 MIS-C hospitalized patients were included. Children with MIS-C were older than those with KD. A higher frequency of male sex was noted in both groups, with no significant differences in race and ethnicity (Table). MIS-C children frequently presented with symptoms similar to KD (63.5% rash, 55.8% conjunctivitis, 28.9% mucous membrane changes);however, only one MIS-C patient met criteria for complete KD (Figure). Both MIS-C and KD children presented with elevated CRP and ESR, but the median value of CRP in MIS-C children was significantly higher (Table). In addition, white cell count was lower in MIS-C children, which is primarily driven by the lower absolute lymphocyte count in this group (0.9 vs 2.7, p< 0.001), and echocardiography was more likely to be abnormal at presentation compared to KD (Table). Conclusion. MIS-C and KD present similarly in children;however, age, laboratory and echocardiography findings can help differentiate between them. Different laboratory values suggest different pathophysiology and inflammatory mediators behind these two illnesses, warranting further research.

Comparison of Humoral Immune Response to the SARS-CoV-2 BNT162b2 Vaccine between Solid Organ Transplant Recipients and Healthy Controls

Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased morbidity and mortality in immunocompromised individuals, including solid organ transplant recipients (SOTR). Despite being excluded from phase 1-3 SARS-CoV-2 vaccine clinical trials, SOTR were identified as high-risk populations and prioritized for vaccination in public health guidelines. We aimed to evaluate the antibody response to two doses of the BNT162b2 (Pfizer-BioNTech) vaccine in SOTR as compared to healthy controls (HC). Methods. SOTR and HC scheduled to receive two doses of BNT162b2 vaccine and able to complete required follow-up visits were enrolled. Blood specimens were collected from participants before receiving the first and second doses and 21-42 days after the second dose. Enzyme-linked immunosorbent assay (ELISA) was used to detect immunoglobulin G (IgG) to the SARS-CoV-2 spike receptor-binding domain (RBD). Generalized estimating equations with a working independence correlation structure were used to compare anti-RBD IgG levels between SOTR and HC at each study visit and within each group over time. All models were adjusted for age, sex, and pre-vaccination seroreactivity in the ELISA. Results. A total of 54 SOTR and 26 HC were enrolled, with mean (SD) ages of 72 (3.6) and 62 (6.7) years, 61% and 35% were male, and 91% and 88% were white, respectively. The most common organ transplant types were kidney (41%) and liver (37%). All SOTR were receiving calcineurin inhibitors. The median time post-transplantation was 7 years. SOTR had markedly lower mean anti-RBD IgG levels when compared to HC with adjusted mean differences of -0.76 (95%CI: [-1.04, -0.47];p < 0.001) ELISA units (EU) and -1.35 (95%CI [-1.68, -1.01];p < 0.001) EU after the first and second doses, respectively (Figure 1). Both groups had a significant increase in anti-SARS-CoV-2 IgG levels after the second dose. However, the magnitude was lower in SOTR, 0.49 (95%CI [0.31, 0.69];p < 0.001) EU than in HCs, 1.08 (95% CI [0.91, 1.24];p < 0.001) EU. Figure 1. Anti-SARS-CoV-2 RBD IgG levels in solid organ transplant recipients and healthy controls before receiving the BNT162b2 vaccine (baseline), post-vaccine dose 1, and post-vaccine dose 2. Conclusion. Our study showed SOTR mounted weaker humoral immune responses than HC to SARS-CoV-2 vaccines. Given a lower response, SOTR should continue to practice social distancing and masking until data on vaccine efficacy are available in this vulnerable population.

COVID-19 Vaccine Perceptions in Adults from Greater Nashville Tennessee

Background. In December 2020, SARS-CoV-2 vaccines were made available to healthcare workers and soon thereafter offered to the general public according to age and risk of severe illness. Despite widespread access, vaccination rates vary by region, with Tennessee ranking lower than the national average. Therefore, we aimed to survey adults in greater Nashville, TN regarding SARS-CoV-2 vaccine perceptions. Methods. We conducted a cross-sectional study of an ongoing longitudinal cohort of individuals with confirmed and/or suspected SARS-CoV-2 infection and their household contacts with enrollment onset in March 2020. For this analysis, individuals were included if they were ≥ 18 years and available for a one-year follow-up visit. At the one-year visit individuals completed a survey about vaccine preferences, beliefs and risks. Demographic and social characteristics were collected at enrollment. Individuals were considered vaccinated if they had received at least one dose of a SARS-CoV-2 vaccine under FDA emergency use authorization. Vaccine perceptions were compared by SARS-CoV-2-infection and vaccination status using Pearson's chi-squared, alpha=5%. Results. Between April-May 2021, 115 individuals completed the one-year follow-up. Table 1 includes sociodemographic characteristics of adults, of which the majority were vaccinated and were unemployed or in non-essential occupations. Most individuals agreed the SARS-CoV-2 vaccine can prevent infection and hospitalization (Figure 1A & B). Unvaccinated participants more often agreed that those who contracted SARS-CoV-2 should not receive the vaccine (30%), whereas vaccinated persons less often agreed (11%, p< 0.001) (Figure 1A). Additionally, 44% of unvaccinated individuals were neutral or disagreed that benefits of SARS-CoV-2 vaccination outweighed the illness risk, compared to 10% in the vaccinated group, p=0.001 (Figure 1A). Minimal differences of vaccine perceptions were observed between SARS-CoV-2 positive and negative adults (Figure 1B). Conclusion. Although some unvaccinated individuals seemingly perceived the SARS-CoV-2 vaccine offered some protection, research should continue to evaluate the implications of vaccine hesitancy on the COVID-19 pandemic response as we prepare for the upcoming respiratory season.

Comparison of Singleplex qPCR and the Luminex MAGPIX Platform for the Detection of Viral Pathogens

Background: Various respiratory molecular assays are available, each with different characteristics and advantages that make them uniquely valuable. The objective of this study was to compare rates of viral detection using singleplex and multiplex platforms in a research setting. Methods: A prospective viral surveillance study was conducted in Davidson County, TN. Infants under one year who presented with fever and/or respiratory symptoms were enrolled from the outpatient, emergency department and inpatient settings. Nasal swabs were collected and tested for influenza A (FluA), influenza B (FluB), human metapneumovirus (MPV), respiratory syncytial virus A and B (RSVA and RSVB), human adenovirus (AdV), parainfluenza 1, 2, 3, and 4 (PIV1-4) and SARS-2-CoV by both singleplex qPCR and the Luminex NxTAG Respiratory Pathogen and NxTAG CoV Extended panels. The rhinovirus/enterovirus, human bocavirus, Chlamydophila pneumoniae, Mycoplasma pneumoniae and coronavirus HKU1, NL63, 229E and OC43 results from the Luminex panel were excluded because singleplex qPCR was not performed on those targets. For singleplex qPCR results, cycle threshold (Ct) values were used as a surrogate for viral load, with a higher Ct value indicating a lower viral load. Results: A total of 112 nasal specimens were tested by both singleplex qPCR and Luminex, of which 65 were positive for at least one virus by either platform and 56 had a virus detected on both platforms (Figure 1). Seven specimens were positive by singleplex qPCR only and two were positive by Luminex only (Figure 1). The targets positive by singleplex qPCR only included FluB, RSVA, AdV and PIV2 and those positive by Luminex only included FluA H1N1 and RSVB (Figure 2). Specimens that were positive only on the singleplex assay had a higher average Ct value than those that were positive on both assays, indicating a lower viral load (Figure 3). Figure 1 Figure 2 Figure 3 Conclusion: The multiplex assay identified 89% of the total viruses detected while singleplex qPCR identified 97% of the total viruses detected. Lower viral loads may contribute to false negative results on the multiplex platforms. Future studies with larger sample sizes are needed in order validate our findings.

Outbreak of COVID-19 among school auction attendees: Was it a “silent auction” or “silent transmission”?

Background: One day after the pandemic was announced, Tennessee declared a state of emergency on March 12, 2020 with implementation of a stay-at-home order on March 23, 2020. Data regarding the routes and patterns of community transmission of SARS-CoV-2 are limited. We initiated an investigation after clusters of confirmed COVID-19 cases attended a large social gathering. Methods: We were notified of clinical providers who attended a “Silent School Auction” on March 7, 2020, of which several confirmed-cases were identified as targeted participants. To derive a standardized REDCap web-survey, we conducted a hypothesis-generating interview with three confirmed attendees to collect event details. Once finalized, enrollment included collecting sociodemographic, epidemiologic, and clinical data. Attendees were classified as: 1) confirmed if they had a positive SARS-CoV-2 test;2) suspected if they developed symptoms 21-days before or after the auction;and 3) asymptomatic if no symptoms were noted. Results: From March 20-June 16, 100/166 (60%) of attendees were enrolled, with a median age of 41 years, 54% female, and 99% white. Of those, 34 and 32 were confirmed- and suspect-cases, respectively. Table 1 compares sociodemographic behaviors of all attendees, with the majority of confirmed-cases eating late in the evening. From March 6 to March 8, 58 participants reported attending other social events, of which three (i.e., church service, women's retreat, and a birthday party) were common among 43 attendees and five individuals reported onset of mild respiratory symptoms prior to the event (Figure 1). Confirmed-cases were more likely to report having shortness of breath, chest tightness, loss of taste, loss of smell, and fever compared to suspect-cases (Figure 2) and no one required hospitalization. Dining tables from the school auction depicted a clustering of cases occurring at each table, with some individuals visiting more than one table during the event (Figure 3). Conclusion: We identified several COVID-19 cases from a single event that occurred prior to social mitigation strategies. Our investigation highlights the importance of staying home when sick and the significance of social distancing to halt transmission of COVID-19. (Table Presented).

Clinical characteristics of SARS-CoV-2 among confirmed and suspected cases in Tennessee

Background: On March 11, 2020, a pandemic due to SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), was declared. The disease spectrum varies from asymptomatic detection to severe disease. Data on community versus hospitalized cases are limited. We aim to evaluate and compare the epidemiological and clinical characteristics associated with SARS-CoV-2 infection among suspected and confirmed COVID-19 cases primarily diagnosed in the ambulatory setting and compare their illness presentation. Methods: We are prospectively enrolling a longitudinal cohort of laboratory- confirmed or suspected COVID-19 subjects and their close contacts. Suspect cases are defined as anyone who developed fever and/or Covid-19 like-symptoms in the post-Covid-19 era without proven SARS-CoV-2 detection. We consented and interviewed subjects over the phone to capture detailed sociodemographic data, medical and social histories, and clinical characteristics of the illness. Results: From March 20 to June 16, 2020, 463 subjects were enrolled (Figure 1). Of those, 178 were SARS-CoV-2 positive [164 adults and 13 pediatric (< 18 years) cases] and 192 were COVID-19 suspected (111 adults and 78 pediatric cases). Adult confirmed cases were more likely to be Hispanic and have an underlying medical condition but less likely to be white compared to suspected cases (Table 1). Pediatric confirmed cases were more likely to be Hispanic and have smoke exposure, but less likely to have a travel history compared to suspected cases (Table 1). Both adult and pediatric confirmed subjects had fatigue, headache and cough as the most common symptoms reported. Cough, muscle aches and chest tightness were more likely to be reported in pediatric confirmed than suspected cases;whereas loss of taste, smell and appetite, diarrhea and fever ≥ 100.4 were documented more often in adult confirmed than suspected cases (Figure 2). Conclusion: We observed differences of clinical presentation between confirmed and suspected cases among both pediatric and adult participants. Further research is needed to determine whether these differences are due to disease severity or absence of proven COVID-19. We are collecting serial nasal swabs, blood and stool specimens, on which future testing will confirm SARS-CoV-2 infection in suspected subjects. (Figure Presented).